Treatment of Apathy in Alzheimer's Disease With Modafinil: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Apathy in Alzheimer's Disease With Modafinil (NCT01172145), a randomized phase 3 study. The primary outcome is Apathy.

2. Clinical Question

The central statistical contrast is between participants assigned to the cholinesterase-inhibitor-only group and those assigned to the group receiving cholinesterase inhibitor plus modafinil. The posted baseline means describe the groups at baseline, not change over time. They therefore cannot, by themselves, show whether the groups changed differently during the trial. The registry record does not report the treatment duration, follow-up schedule, or a detailed account of the planned primary analysis.

3. Trial Design

The registry identifies this as a randomized, triple-masked, parallel-group Phase 3 trial. It lists Brown University as the sponsor and the study status as completed. The recorded start is 2005-07. Enrollment was 22, and the posted outcome summaries include 11 participants in each group.

The two posted groups were titled “Cholinesterase Inhibitor Only” and “Cholinesterase Plus Modafinil.” This is the clearest description of the comparison available in the record. Although placebo is listed among the interventions, details of how it was used are not reported in the registry record. The meaning of triple masking in practice, including which people were masked, is not reported. Allocation concealment, treatment duration, and procedures for maintaining masking are also not reported in the registry record.

The study summary says it examined apathetic symptomatology, performance of activities of daily living, and caregiver burden in individuals with Alzheimer's disease. The primary outcome is listed as apathy measured with the Frontal Systems Behavior Scale. The registry lists the Lawton Brody Activities of Daily Living Questionnaire, the Direct Assessment of Functional Status Scale, and the Zarit Burden Inventory among the secondary outcomes. Posted secondary outcome summaries are at baseline.

The registry record does not report the original sample-size justification, eligibility criteria, participant characteristics, or details of the randomization procedure. It also does not report a protocol or a complete account of how outcome measurements were scheduled. These omissions limit what can be concluded about how closely the posted results correspond to the trial's original design.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Apathy, measured over at baseline.

The primary outcome is apathy measured with the Frontal Systems Behavior Scale. The posted measure is a T-score, with a mean and standard deviation, and the listed timeframe is baseline. The registry says raw scores are converted to T-scores using published norms. It describes a T-score mean of 50 and standard deviation of 10; scores less than or equal to 64 are within the average range, while scores equal to or greater than 65 indicate a clinically significant problem. Higher scores indicate greater problem severity.

This measure is relevant to the study's stated focus on apathetic symptoms in people with Alzheimer's disease. A standardized score allows the reported severity to be interpreted against the norms described in the registry. The score's direction also matters: higher values represent greater problem severity, not improvement.

The timing is important for interpreting the reported group means. Because the primary outcome entry specifies baseline, its means describe the groups at the start of the study rather than a treatment response. The registry separately reports a sponsor t-test of final values, but does not specify how those final values relate to the primary outcome entry or whether they represent a change analysis. The endpoint description does not include a reported change-from-baseline estimate.

7. Results Posted in the Registry

• Cholinesterase Plus Modafinil: mean 95.64 versus 88.91 on control; difference 6.73 (95% CI -2.78 to 16.24), standardized effect d = 0.59; z-test p = 0.166.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Lawton Brody Activities of Daily Living Questionnaire

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Cholinesterase Plus Modafinil: mean 16.18 versus 19.00 on control; difference -2.82 (95% CI -7.03 to 1.39), standardized effect d = -0.56; z-test p = 0.189.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cholinesterase Plus Modafinil and the control. The interval gives the range of effects that remain compatible with the data.

The Direct Assessment of Functional Status Scale

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Cholinesterase Plus Modafinil: mean 84.55 versus 89.09 on control; difference -4.54 (95% CI -15.13 to 6.05), standardized effect d = -0.36; z-test p = 0.401.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cholinesterase Plus Modafinil and the control. The interval gives the range of effects that remain compatible with the data.

Zarit Burden Inventory

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Cholinesterase Plus Modafinil: mean 31.18 versus 28.36 on control; difference 2.82 (95% CI -10.67 to 16.31), standardized effect d = 0.17; z-test p = 0.682.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cholinesterase Plus Modafinil and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover activities of daily living, functional status, and caregiver burden. Their group contrasts point in mixed directions rather than forming one consistent pattern across all measures. The intervals for the posted unadjusted comparisons include zero, so the summaries do not precisely establish the direction or size of baseline group differences. As with the primary outcome, these entries are baseline measurements, not estimates of differences in change during treatment.

This pattern does not resolve the primary question. The primary outcome is also reported at baseline, and the sponsor's final-values analysis is a separate result whose relationship to the baseline summaries is not explained. Secondary measures can provide context about the range of domains assessed, but their baseline values cannot establish whether treatment changed those domains.

The registry lists six secondary results as posted, while the outcome list contains repeated measure names. It reports no sponsor analyses for the secondary outcomes. The unadjusted comparisons should therefore be treated as descriptive rather than as a set of confirmatory findings. When multiple outcomes are examined, the chance of at least one apparently notable result can increase; in general, multiplicity procedures or a clearly prespecified hierarchy help address that issue. The record does not report whether such procedures were planned or used. The combination of multiple measures, small groups, baseline-only summaries, and absent reported analyses means the secondary results carry less weight for judging treatment effects than a clearly specified, appropriately analyzed primary endpoint would.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Lawton Brody Activities of Daily Living Questionnaire
• The Direct Assessment of Functional Status Scale
• Zarit Burden Inventory
• Lawton Brody Activities of Daily Living Questionnaire
• The Direct Assessment of Functional Status Scale
• Zarit Burden Inventory

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous and is summarized by group means and standard deviations. A mean describes the arithmetic average of the observed scores; a standard deviation describes how spread out the scores are around that average. The posted values give both kinds of summaries for each group. In general, a mean difference expresses the contrast between two group averages. The recalculated contrast is defined as the modafinil group mean minus the cholinesterase-inhibitor-only group mean, so a positive value indicates a higher average in the modafinil group.

The registry reports a sponsor analysis using a two-sided t-test of final values. A t-test evaluates how compatible an observed difference in means is with a null hypothesis of no difference, under its statistical assumptions. “Two-sided” means that differences in either direction are considered. The registry lists the sponsor's mean difference, confidence interval, and p-value. It does not report whether the test was adjusted for baseline values, what assumptions were checked, or whether another model was used for the primary analysis.

The recalculated comparison is a simple, unadjusted comparison based on the posted group summaries. It is not a replacement for a prespecified sponsor analysis. Its estimate and uncertainty are useful for describing the posted baseline values, but should not be read as a treatment-effect analysis. The record does not report enough information to reconstruct an adjusted analysis or to establish that the baseline comparison and final-values test target the same question.

What does a p-value describe?

In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test's assumptions were true. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. Here, the recalculated baseline comparison has p = 0.166, and the sponsor's final-values analysis has p = 0.181. Neither value alone establishes that there is no difference, nor does either show that a treatment effect exists.

What does a confidence interval add?

In general, a confidence interval gives a range of estimates that are reasonably compatible with the observed data and the method used to calculate the interval. Its width communicates precision: wider intervals leave more uncertainty about the size and direction of the difference. The intervals for both the recalculated baseline comparison and sponsor analysis include zero. That indicates that a zero difference is compatible with each analysis, while the surrounding values also allow for differences in either direction. A confidence interval does not correct for a mismatch in timepoint or answer whether the analysis was prespecified.

Why does variability matter?

In general, greater variation in outcome scores makes a group mean less precisely estimated when the sample size is held fixed. The standard deviations in these groups describe variability in individual scores, while the confidence interval reflects uncertainty in the difference between group means. Small groups can produce wide intervals even when the point estimate appears substantial. The registry does not report distribution checks or further diagnostics, so it is not possible to assess the t-test assumptions from the posted summaries alone.

What is not described about the analysis?

The registry record does not report the original sample-size justification, a complete statistical analysis plan, interim analyses, analysis populations, or missing-data methods. It does not state whether multiplicity adjustments were planned, whether the primary comparison was adjusted for baseline scores, or how protocol deviations were handled. Those details matter because they clarify which analyses were planned, how incomplete records were treated, and how to interpret multiple outcome tests. Their absence limits interpretation of the reported results, but does not itself show that a particular method was or was not used.

11. Confidence Intervals and Precision

The recalculated baseline mean difference is 6.73, with a 95% confidence interval from -2.785 to 16.24. The interval includes zero and extends to values in both directions. It therefore does not pinpoint whether the baseline group averages differed, nor does it tightly determine the size of any difference. The interval reflects uncertainty in the comparison of the posted baseline means; it is not a confidence interval for a change over time.

The sponsor's final-values analysis reports a mean difference of -1.385 with a 95% confidence interval from -16.86 to 3.40. This interval also includes zero and covers a broad range of possible differences. Because the registry does not explain how the final-values analysis relates to the baseline outcome summaries, its precision should be considered separately rather than combined with the baseline estimate.

In general, a confidence interval describes the range of values compatible with an estimate under the calculation method and its assumptions. A wider interval indicates less precision, not necessarily a flawed analysis. The small posted group sizes are relevant to precision, but the registry does not provide enough information to determine how much of the uncertainty reflects sample size, score variability, or other features of the data. Neither interval is proof of equivalence: demonstrating equivalence requires a defined margin and a suitable analysis, neither of which is reported in the registry record.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrative calculations based on the observed effect, not the trial's original design assumptions. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The original design assumptions and the trial's sample-size justification are not reported in the registry record.

The 80% power column describes the number of participants per arm estimated to give an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the assumptions hold. The 90% power column describes the corresponding estimate for a 90% chance. These are planning targets, not guarantees about what a future study will find. The rows describe planning for the full observed effect, 75% of the observed effect, and 50% of the observed effect. Smaller effects need more participants to reach the same power target, which is why the estimates increase as the fraction of the observed effect decreases.

These figures are not observed power. They do not show the chance that this completed trial detected an effect, and they do not establish that the observed effect is a reliable estimate for planning another study. The calculations use an effect estimated from a small set of posted group summaries; the planning figures should therefore be read as illustrations rather than precise recommendations. They also do not establish that the trial was originally designed around these assumptions.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 6.730; pooled standard deviation σ = 11.385.
2. n = 2 × (1.96 + 0.842)² × 11.385² / 6.730² = 44.9, rounded up to 45 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 6.73                      # observed difference in means
sigma <- 11.3847837045769                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1172145)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 45 (80% power), 61 (90% power)
 75% of observed effect: n per arm = 80 (80% power), 107 (90% power)
 50% of observed effect: n per arm = 180 (80% power), 241 (90% power)
power.t.test: 45.9 
Simulated power at n = 45 per arm: 0.789 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports the sponsor's own analysis as a two-sided t-test of final values. The reported mean difference is -1.385, with a 95% confidence interval from -16.86 to 3.40 and p = 0.181. The interval includes zero, so the posted sponsor analysis does not precisely establish the direction or size of a final-values difference.

The unadjusted recalculation uses the posted baseline group means and standard deviations. It gives a mean difference of 6.73, a 95% confidence interval from -2.785 to 16.24, and p = 0.166. Since the registry identifies one comparison as baseline and the sponsor's analysis as final values, these estimates do not necessarily concern the same timepoint or estimand. The record does not explain the relationship between them, or report a change-from-baseline analysis.

The recalculation is a simple check based on summary statistics, not a substitute for the sponsor's analysis. The sponsor-reported result is the registry's stated test of final values; interpretation of its intended role is limited because the analysis plan is not reported. Neither result should be used to claim that a treatment effect was present or absent without further information about the protocol, outcome timing, and analysis methods.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and multiple secondary outcome measures. It reports eight outcome measures overall and six posted secondary results. The record does not report whether the outcome hierarchy was prespecified, whether a multiplicity adjustment was planned, or how the sponsor handled multiple statistical tests. Without those details, individual unadjusted p-values should not be interpreted as if they were protected against the chance findings that can arise when many outcomes are examined.

The analysis population is not reported in the registry record. Although 22 participants were enrolled and each posted group summary includes 11 participants, the record does not say whether every randomized participant was included in the sponsor's analysis, whether any participants were excluded, or how the analysis population was defined. The posted group counts alone do not establish the handling of participants with incomplete outcome data.

Missing-data methods are also not reported. The record does not describe whether outcome data were missing, how missingness was assessed, or whether any imputation or other handling method was used. It does not report sensitivity analyses to examine the effect of missing observations. These omissions matter because conclusions from a group comparison can depend on who contributes data and how incomplete records are handled.

The registry record does not report the statistical analysis plan, the original sample-size justification, interim analyses, or whether the primary comparison was adjusted for baseline values. It also does not explain how the sponsor's final-values analysis relates to the baseline outcome entry. These unreported details limit assessment of prespecification and robustness; their absence should not be taken as evidence that a particular procedure was or was not performed.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures show 0 participants affected among 11 at risk in the cholinesterase-inhibitor-only group and 0 among 11 at risk in the cholinesterase-plus-modafinil group. No serious adverse event terms are listed. These counts describe what is posted for the groups; they do not show that the risk of a rare event was absent.

For other adverse events, the registry reports 0 participants affected among 11 at risk in the cholinesterase-inhibitor-only group and 1 among 11 at risk in the cholinesterase-plus-modafinil group. Death counts are not reported in the registry record. The record does not give further detail about event types, timing, severity, relatedness, or how adverse events were collected.

With 11 participants per group, these figures provide a limited account of safety events. The counts should not be read as a comprehensive assessment of safety or as evidence about risks beyond the events and period captured in the registry entry.

17. What the Result Does, and Does Not, Mean

The posted results establish that the registry contains baseline group summaries for apathy and several secondary measures, along with a sponsor-reported t-test of final values for the primary outcome. The baseline apathy means are higher in the modafinil group, while the unadjusted interval spans zero. The sponsor's final-values interval also spans zero. Together, these findings leave substantial uncertainty about the direction and size of group differences.

They do not establish whether modafinil changed apathy, activities of daily living, functional status, or caregiver burden. The posted outcome summaries are at baseline, and the registry does not report change-from-baseline estimates. The sponsor's final-values analysis is not explained in enough detail to determine its relationship to those baseline summaries. Thus, the available results do not provide a clear treatment-effect estimate that can be interpreted as a change caused by assignment.

The findings also do not demonstrate equivalence or prove that an effect is absent. The confidence intervals include zero, but also include values in either direction. The registry does not report an equivalence margin or a noninferiority analysis. Likewise, statistical uncertainty and clinical importance are distinct: the score description gives context for interpreting severity, but the record does not define a threshold for a clinically important difference between groups.

The small posted group sizes, lack of reported analysis details, and missing information about participant characteristics and follow-up constrain interpretation. The safety counts describe few reported events in the posted groups but cannot establish the absence of less common harms. Overall, the registry results should be understood as limited statistical evidence about this trial's recorded outcomes, not as medical advice or a conclusion about treatment for an individual.

18. Why This Trial Matters Statistically

This trial illustrates why the timing attached to an outcome is essential. The primary outcome is labeled at baseline, while a sponsor analysis is identified as a comparison of final values. Those are not automatically the same statistical question. Without a reported change analysis or an explanation of the analysis plan, a baseline group contrast should not be mistaken for a treatment effect.

It also shows why estimates and their uncertainty should be read together. A point estimate gives a direction and scale, but the confidence intervals indicate that a broad range of differences remains compatible with the posted summaries. A p-value alone cannot communicate that range, establish equivalence, or measure clinical importance.

The contrast between the posted baseline summaries and the sponsor's reported analysis also highlights the need for clear reporting of outcome timing and estimands. Readers need to know whether an analysis compares final values, change from baseline, or an adjusted outcome, and how the analysis population was defined. Those details are not reported in the registry record.

Finally, planning illustrations based on an observed effect can be useful for understanding how assumed effect size and power targets affect sample-size estimates. They are not the original design rationale and should not be mistaken for observed power. With a small trial and limited analysis details, the most statistically responsible reading emphasizes uncertainty, distinguishes descriptive from inferential results, and avoids turning a nonsignificant test into a claim of no effect.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations specific to this record affect interpretation. The posted primary measure is described at baseline, but the sponsor's reported analysis is of final values. The registry does not explain how these entries relate, report a change-from-baseline estimate, or identify whether the final-values test was the prespecified primary analysis. As a result, the available statistics do not clearly quantify the treatment contrast over time.

Only 11 participants are included in each posted group summary. The resulting confidence intervals are broad, leaving considerable uncertainty about the size and direction of the group differences. The record does not report participant characteristics or eligibility criteria, so it is not possible to assess how representative the enrolled participants were of a wider population.

Important design and analysis details are absent: treatment duration, dosing, randomization procedures, the meaning of triple masking, the analysis population, missing-data methods, and the original sample-size justification are not reported in the registry record. The record also does not report whether the primary analysis adjusted for baseline values or whether multiplicity was addressed.

Secondary outcomes are listed with baseline summaries, and no sponsor analyses are posted for them. These data offer limited information about treatment effects. Safety reporting is also sparse: the registry gives group counts for serious and other adverse events, but does not report deaths or additional event details. These limitations do not prove that unreported procedures or analyses were absent; they mark what cannot be evaluated from the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Treatment of Apathy in Alzheimer's Disease With Modafinil — NCT01172145.
• Registry record last updated 2011-03-04; status last verified 2010-09.
• Results first posted 2011-03-04.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

The registry describes a completed, randomized, triple-masked, parallel-group Phase 3 trial sponsored by Brown University, with 22 participants enrolled and a recorded start of 2005-07. The comparison was cholinesterase inhibitor only versus cholinesterase inhibitor plus modafinil.

The primary outcome is apathy measured by the Frontal Systems Behavior Scale, listed at baseline. The posted baseline group summaries have 11 participants per group. The registry also reports a sponsor two-sided t-test of final values, but does not explain its relationship to the baseline entry. Its reported confidence interval includes zero, as does the interval from the unadjusted baseline recalculation.

Secondary outcomes address daily activities, functional status, and caregiver burden, with baseline summaries posted. Serious adverse events were reported for 0 participants in either group; other adverse events were reported for 0 in the comparator group and 1 in the modafinil group. The registry does not report the original sample-size justification, missing-data methods, analysis populations, or a complete statistical analysis plan. The posted results therefore leave uncertainty about treatment effects and the intended analysis.